Thiosemicarbazone iron chelators are a class of anti-cancer agents that have been found to be extremely potent and selective against a number of different neoplasms both in vitro and in vivo. These compounds function by targeting iron, an essential element for DNA synthesis, in cancer cells. Iron chelators were initially developed for iron-overload diseases such as β-thalassemia, with the chelator desferrioxamine (DFO) being the most widely used treatment for this disease. However, clinical trials examining DFO against neuroblastoma found that this agent was effective at inhibiting the progression of this cancer in some patients. These early studies were the first to identify the potential of iron chelators as anti-cancer agents. Since then, iron chelators designed specifically for the treatment of cancer have been developed, with the thiosemicarbazone iron chelator 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine®) (Vion Pharmaceuticals, New Haven Conn., United States of America) entering a number of phase I and II clinical trials.
Thiosemicarbazone iron chelators function by binding iron and copper and forming redox-active complexes, leading to the production of reactive oxygen species (ROS) that induce cancer cell cytotoxicity. One of the most active compounds developed to date is a thiosemicarbazone class of iron chelator, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone, (abbreviated herein as Dp44mT), which is described in WO 2004/069801. Dp44mT has been demonstrated to markedly and significantly reduce the growth of a number of different tumors in vitro and in vivo and was found to be more potent and less toxic than Triapine®. However, studies using high, non-optimal doses of Dp44mT found that it induced some cardiotoxicity in nude mice.
Thiosemicarbazone compounds target the metastasis suppressor, NDRG1. NDRG1 inhibits both growth and metastasis as well as angiogenesis of pancreatic cancer in vivo leading to reduced tumor progression. Moreover, NDRG1 has also recently been correlated with increased differentiation of pancreatic cancers and its potential as a promising therapeutic target against pancreatic cancer has been reported (eg, Kovacevic, Z. and D. R. Richardson (2006). Carcinogenesis 27: 2355-66; Maruyama, Y., M. Ono, et al. (2006). Cancer Res 66: 6233-42). NDRG1 has a number of key molecular targets in pancreatic cancer including the tumor suppressors PTEN and SMAD4, both of which are up-regulated in response to NDRG1. Therefore, NDRG1 may be a promising therapeutic target, especially for the treatment of pancreatic cancer. NDRG1 was recently found to be up-regulated using iron-chelating anti-cancer agents in vitro and in vivo. Iron chelators increased NDRG1 expression via hypoxia-inducible transcription factor (HIF-1)-dependent mechanisms, although HIF-1-independent pathways have also been observed. Iron-chelating anti-cancer agents therefore provide an important opportunity to target NDRG1 expression in cancer cells by cellular iron depletion.
There is a need for new and alternative treatments for cancer. The present invention is directed to a selection of thiosemicarbazone compounds that advantageously inhibit cellular proliferation and may be useful for the treatment of cancer.